Tag Archives: focused ultrasound

Focused Ultrasound for Brain Tumors: Hope for the Future of GBM

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In John Grisham’s book The Tumor, he tells a story of the typical clinical pathway and trajectory of a patient diagnosed with glioblastoma (GBM), a devastating brain tumor. Then, he sets the stage for a re-imagination of this patient’s clinical course if focused ultrasound were added to his treatment armamentarium. What this could look like is less suffering, longer life expectancy, and cost savings.

Glioblastoma has a 90% mortality rate within 5 years of diagnosis. This disease has lacked any significant improvement in survival in over 30 years, despite scientific advances in many areas, such as molecular subtyping, tailored chemotherapy regimens, and immunotherapy. The current standard-of-care treatment for GBM includes surgical resection, chemotherapy, and radiation.

Focused ultrasound is an emerging therapeutic technology that has the potential to change the treatment landscape and clinical trajectory for a multitude of diseases and conditions, including GBM. The fascinating thing about focused ultrasound is that scientists and clinicians have discovered that the properties of the ultrasound energy can be manipulated in such a way as to induce a variety of different biological effects and mechanisms of action. The technology was initially designed to thermally ablate tissue, but since that time, more than 20 mechanisms of action have been identified.

In GBM, there are three focused ultrasound mechanisms of action that are being employed as an adjunct or complement to traditional therapies: opening of the blood-brain barrier (BBB), sonodynamic therapy (SDT), and radiation sensitization or enhancement (Figure 1).1,2

Figure 1: Focused Ultrasound (FUS) Mechanisms of Action related to brain tumor therapy (A) Blood Brain Barrier Opening (BBBO): In the presence of focused ultrasound, intravenously injected microbubbles oscillate inside the brain’s blood vessels and stretch the tight junctions, allowing therapeutics to diffuse into the targeted region. Not depicted here are the additional mechanisms of sonoporation and increased transcytosis, which also occur with FUS-mediated BBBO. (B) Sonodynamic Therapy: Intravenous injection of a sonosensitizer such as 5-ALA accumulates preferentially inside brain tumor cells. Conversion of the sonosensitizer into an active substrate (ie PpIX) induces tumor cell death. (C) Radiation Sensitization: The proposed mechanism of action involves ceramide-induced endothelial apoptosis, which subsequently enhances radiation by causing vascular disruption. Distortion of the endothelial cell membrane by oscillating microbubbles in the presence of the FUS beam releases ceramide, which then causes platelet aggregation and thrombosis.

The most clinically advanced of these three focused ultrasound mechanisms is BBB opening, which is currently being investigated in numerous clinical trials that combine this technique with delivery of chemotherapeutic agents.3–5 Thus far, safety and efficacy have been confirmed, and I am excited to see additional clinical trial results. SDT clinical trials are also underway and have shown promise. Lastly, using focused ultrasound to enhance radiation is being investigated.

There are also a variety of focused ultrasound devices being investigated for use, from MRI-guided to neuronavigation-guided to implantable devices. Each system offers unique benefits and challenges, which continue to be elucidated through ongoing clinical work.

One more promising frontier for focused ultrasound and GBM is liquid biopsy. Just as focused ultrasound plus microbubbles can disrupt the BBB to allow the passage of therapeutics into the tumor, this method also allows for the leakage of tumor biomarkers into the blood from the tumor, enabling enhanced diagnosis and monitoring methodologies for GBM.6

While this blog post provides a brief overview of focused ultrasound for GBM, it hopefully conveys that the technology is ripe for helping patients live longer, more comfortable lives. The Focused Ultrasound Foundation is on a mission to engage and convene the scientific and medical communities to make this happen as quickly, safely, and effectively as possible so that the fictional character that Grisham described can become a reality.

Author’s note: The Foundation is also enthusiastic about using this technology in a similar fashion for children with diffuse intrinsic pontine glioma (DIPG)/diffuse midline glioma (DMG), and this area has experienced significant growth over the past year. To learn more, visit the Foundation’s webpage dedicated to DIPG/DMG.

References

  1. Roberts JW, Powlovich L, Sheybani N, LeBlang S. Focused ultrasound for the treatment of glioblastoma. J Neurooncol 2022; 157(2):237–247. doi: 10.1007/s11060-022-03974-0. Epub 2022 Mar 10. PMID: 35267132; PMCID: PMC9021052.
  2. Parekh K, LeBlang S, Nazarian J, et al. Past, present and future of focused ultrasound as an adjunct or complement to DIPG/DMG therapy: A consensus of the 2021 FUSF DIPG meeting. Neoplasia 2023; 37:100876. doi: 10.1016/j.neo.2023.100876. Epub 2023 Jan 28. PMID: 36709715; PMCID: PMC9900434.
  3. Bunevicius A, McDannold NJ, Golby AJ. Focused ultrasound strategies for brain tumor therapy. Oper Neurosurg 2020; 19:9–18. doi: 10.1093/ons/opz374
  4. Mainprize T, Lipsman N, Huang Y, et al. Blood-brain barrier opening in primary brain tumors with non-invasive MR-guided focused ultrasound: a clinical safety and feasibility study. Sci Rep 2019; 9:321. doi: 10.1038/s41598-018-36340-0.
  5. Meng Y, Hynynen K, Lipsman N. Applications of focused ultrasound in the brain: From thermoablation to drug delivery. Nat Rev Neurol 2021; 17:7–22. doi: 10.1038/s41582-020-00418-z. 
  6. Meng Y, Pople CB, Suppiah S, et al. MR-guided focused ultrasound liquid biopsy enriches circulating biomarkers in patients with brain tumors. Neuro Oncol 2021; 23:1789–1797. doi: 10.1093/neuonc/noab057.

Lauren Powlovich, MD, MBA(c), serves as Associate Chief Medical Officer at the Focused Ultrasound Foundation (FUSF). She brings together key stakeholders and synthesizes and executes cohesive plans to lead initiatives in the advancement of focused ultrasound for several applications including glioblastoma, neurodegenerative disorders, pediatrics, pain management, and sonodynamic therapy. She is a co-leader of the Research and Education Team, which strategizes on the allocation of FUSF’s resources to best position the field for success. Prior to joining the Foundation, Lauren trained as an anesthesiologist, and she has always been passionate about putting patients first. She continues to have that mindset and works hard to ensure that focused ultrasound reaches patients as efficiently and safely as possible.

Live Outside of Your Comfort Zone: Ultrasound Education

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Earlier this year, I attended a new-to-me scientific meeting—the 21st meeting of the International Society for Therapeutic Ultrasound (ISTU) in the beautiful city of Toronto. As I sat in sessions immersed in topics ranging from immunotherapy of liver tumors with histotripsy, to sonogenetic neuromodulation, to focused ultrasound for alleviating the pain from bone metastases, I was overwhelmed. And I was humbled by the vast swaths of knowledge that were nearly completely foreign to me, despite being a senior academic who does research in the field of biomedical ultrasound. I know less about the immune system than I should, and I don’t quite get the nuances of genetics and the brain—well, let’s just say that I like to use mine, but I am unaware of how it all works. I spent a lot of the meeting learning the background to the background of these areas so that I could understand more and better appreciate all the amazing science.

It was a pain and totally out of my comfort zone, but it was exhilarating! I learned so much, and I now appreciate the challenges, opportunities, and potential impact of this field much more than I did before. I met the brilliant physicians and scientists who were all more than willing to enlighten me about the details of their work and their up-and-coming innovations. It was refreshing. As I listened, I thought about the big picture and the potential impact of all this work on patient care and where the field will go in the future.

You may be thinking—why did I choose to attend this meeting? Why did I not go to a conference that was more aligned with my area of research? The answer is simple—I wanted to learn new things. I wanted my students to be exposed to innovative research directions and world experts in a related but distinct area. I wanted to better understand the evidence supporting the research so that I can shape my views with data, not dogma or hearsay. I also contributed a bit by sharing our group’s work on nanobubbles and the lessons we have learned from mostly diagnostic imaging research with these agents that can be applied to therapeutic strategies with focused ultrasound. I am most grateful to the organizers for having the foresight to explore how our research can complement therapeutic ultrasound applications and for inviting me to deliver one of the invited talks. I walked away, ready and inspired to foray into the intimidating world of ultrasound-mediated immunotherapy. Armed with the lay of the land and having met the pioneers of this field, I think the foundations we learned at this meeting will shape the next 5–10 years of our research.

I want to encourage all of you to expose yourself, your colleagues, and your trainees to new concepts, new science, and new clinical approaches. Be open-minded to change, think, consider the evidence, and make rational, data-driven decisions as you move forward with your clinical practice, research, and day-to-day obligations. Educate yourself in the new research and translational directions in the field. The world of biomedical ultrasound is complex, multidisciplinary, and rich with burgeoning ideas that will someday revolutionize clinical practice. Many recent innovations, like the focused ultrasound treatment of essential tremor, are doing so already.

Live outside of your comfort zone—it will refresh and energize you, and it will stimulate new ideas that may someday save one patient, or save the world. Of course, it’s fine to do things as you’ve always done and stay where it’s cozy and comfortable, but I promise you will enjoy it if you venture beyond, even a little bit. Enjoy your summer and science on!

Agata A. Exner, PhD (@AgExner; Agata@case.edu), is the Henry Paine Willson Professor and Vice Chair in the Department of Radiology at Case Western Reserve University & University Hospitals of Cleveland.

Focused Ultrasound and the Blood-Brain Barrier

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When does a barrier protect and when does it hinder? This question is central to the challenge of delivering therapeutics to the brain. For many neuropathologies, the answer is clear: there is a critical need for strategies that can allow clinicians to effectively deliver drugs to the brain. We believe focused ultrasound (FUS) has the potential to be a powerful tool in this quest.

Charissa Poon
Dallan McMahon

Part of this challenge lies in the unique nature of the blood vessels in the brain. The cells that line these vessels are tightly linked together, creating a complex obstacle—called the blood-brain barrier (BBB)—that prevents the vast majority of drugs from entering the brain from the bloodstream. Throughout the years, several strategies of bypassing the BBB have been used, with limited success and many adverse effects. These range from directly inserting a needle into the brain for injections, to the administration of hyperosmotic solutions, which create gaps between cells in the BBB throughout a large volume.

In 1956, Bakay et al successfully ablated brain tumors using high-intensity FUS. In doing so, he observed that the permeability of the BBB was enhanced in the periphery of the ablated tissue. While this was exciting news for BBB enthusiasts, the necessity of damaging tissue in the process of opening the BBB was clearly unacceptable. Several decades later, this approach was successfully modified by administering microbubbles, an ultrasound contrast agent, before sonicating (Hynynen et al 2001). This made it possible to use much lower power levels to produce the desired increase in BBB permeability, thereby avoiding brain damage. By adjusting where the ultrasound energy is focused, specific brain regions can be targeted. For a few hours after treatment, drugs can be administered intravenously, bypass the BBB, and enter the neural tissue in the targeted areas.

Over the past 16 years, many preclinical studies have used FUS to increase the permeability of the BBB, delivering a wide range of therapeutic agents to the brain, from chemotherapeutics and viruses, to antibodies and stem cells. Efficacy has been demonstrated in models of Alzheimer’s disease, Parkinson’s, brain tumors, and others. Moreover, the safety of using FUS to increase BBB permeability has been tested in every commonly used laboratory animal.

The flexibility of FUS as a tool for treating neuropathologies may go beyond the delivery of drugs to the brain. Recently, FUS was shown to reduce the amount of β-amyloid plaques and improve memory deficits in the brains of transgenic mice (Burgess et al 2014, Leinenga and Gotz 2015, Jordao et al 2013).

The success of these preclinical trials has led to the initiation of 3 human trials. Two of these trials are testing the safety of increasing the permeability of the BBB in brain tumors for chemotherapy delivery, and the third is evaluating the safety and initial effectiveness of FUS in patients with early stage Alzheimer’s disease. The rapid movement towards clinical testing has been accompanied by impressive technological advancements in the equipment used to focus ultrasound through the human skull. Arrays of thousands of ultrasound transducers can be controlled to produce sound waves that travel through bone and brain, and arrive at precisely the same time in the targeted location. The sound produced by vibrating microbubbles can be detected and used to ensure the treatment is progressing as planned.

If the barrier to drug delivery to the brain can be bridged by FUS, the development of effective treatment strategies for a wide range of neuropathologies will expand. Given the clear need for such treatments and the flexibility of FUS, the recent push toward clinical testing is encouraging. The coming years will be critical in demonstrating the safety of the technique and spreading awareness. Success in these regards will go a long way in establishing FUS as an impactful tool in the fight against inflictions of the central nervous system.

If you deliver drugs to the brain, how do you do so? Have you found a way to permeate the blood-brain barrier using ultrasound? Comment below or let us know on Twitter: @AIUM_Ultrasound.

Charissa Poon and Dallan McMahon are PhD students at the Institute of Biomaterials & Biomedical Engineering, University of Toronto, and the department of Medical Biophysics, University of Toronto, respectively.

Kullervo Hynynen, PhD, is professor at the department of Medical Biophysics and the Institute of Biomaterials & Biomedical Engineering, University of Toronto, and a senior scientist at Sunnybrook Research Institute in Toronto, Canada.